Synthesis of fatty alcohol esters of alpha-hydroxy carboxylic acids and their use as percutaneous absorption enhancers

ABSTRACT

The present invention provides a novel approach for the preparation of fatty alcohol esters of α-hydroxy carboxylic acids. In one form of the invention, the target fatty alcohol ester of α-hydroxy carboxylic acid is produced by converting a lower alkyl ester of α-hydroxy carboxylic acid into a fatty alcohol ester of α-hydroxy carboxylic acid via alcoholysis (i.e., transesterification). The transesterification process is an equilibrium reaction, catalyzed chemically (i.e., with acids or bases) or enzymatically, that is shifted in the desired direction to produce the desired product. One preferred way of shifting the reaction in the direction of the desired product is by reducing the concentration of one of the products (e.g., distillation of a lower-boiling alcohol as soon as it is formed). Another preferred way of shifting the reaction in-the direction of the desired product is by increasing the concentration of one of the reactants (e.q., adding more of the starting ester).

REFERENCE TO PENDING PRIOR PATENT APPLICATIONS

This patent application claims benefit of:

(i) pending prior U.S. Provisional Patent Application Ser. No.60/619,887, filed Oct. 18, 2004 by Gerald S. Jones, Jr. et al. forSYNTHESIS OF DODECYL LACTATE AND RELATED COMPOUNDS AND THEIR USE ASPERCUTANEOUS ABSORPTION ENHANCERS (Attorney's Docket No. CHEMIC-3 PROV);and

(ii) pending prior U.S. Provisional Patent Application Ser. No.60/698,248, filed Jul. 11, 2005 by Gerald S. Jones, Jr. et al. forSYNTHESIS OF DODECYL LACTATE AND RELATED COMPOUNDS AND THEIR USE ASPERCUTANEOUS ABSORPTION ENHANCERS (Attorney's Docket No. CHEMIC-4 PROV).

The two above-identified patent applications are hereby incorporatedherein by reference.

FIELD OF THE INVENTION

This invention relates to transdermal drug delivery in general, and moreparticularly to a method for the synthesis of fatty alcohol esters ofα-hydroxy carboxylic acids for use as percutaneous absorption enhancers.

BACKGROUND OF THE INVENTION

Transdermal drug delivery (TDD) is the delivery of drugs by absorptionthrough the skin and into the body. TDD has become an established,non-invasive route for both the local and systemic administration ofdrugs.

TDD offers the advantages of smaller drug doses, improved efficacy,reduced toxicity, elimination of first-pass metabolism, minimization ofpain, and possible sustained release.

Despite the obvious advantages of TDD, this delivery approach has notbeen more widely exploited due to the intrinsic barrier properties ofthe skin. Human skin is made up of two layers, the epidermis (i.e., theouter layer) and the dermis (i.e., the inner layer). The stratumcorneum, which is the outermost layer of the epidermis, acts as the mainbarrier to drug delivery. With the discovery and implementation of aneffective means for penetrating this barrier, TDD becomes a moreattractive drug delivery option.

The integrity of the stratum corneum can be disrupted (and hence itspermeability increased) through the use of sound energy, electricalenergy or physical methods. Considerable effort has been concentrated onidentifying non-toxic chemical compounds that will interact with thestratum corneum, thereby increasing the potential for drug penetration.These compounds are sometimes referred to as “permeation enhancers”,“penetration enhancers” or “absorption enhancers”.

A review of the recent patent literature reveals numerous practicalexamples of permeation enhancers used as transdermal delivery devices,including: U.S. Pat. No. Year Assignee Title Enhancer 6699497 2004 AlzaFormulations for the lauryl transdermal lactate; administration ofmyristyl fenoldopam lactate 6638981 2003 EpiCept Topical compositionsTranscutol ® and methods for P treating pain 6582724 2003 Derma- Dualenhancer Transcutol ® trends composition for topical P; Azone ® andtransdermal drug delivery 6156753 2000 Vivus Local administrationAzone ®; of type III SEPA ® phosphodiesterase inhibitors for thetreatment of erectile dysfunction 6118020 2000 NexMed Crystalline saltsof NexACT ® dodecyl 2-(N,N-di- methylamino)propionate 6004578 1999 AlzaPermeation enhancers lauryl for transdermal drug acetate; deliverycompositions, lauryl devices and methods lactate 5843468 1998 Alza Skinpermeation glycerol enhancer compositions monolaurate; comprisingglycerol lauryl monolaurate and acetate lauryl acetate 5314694 1994 AlzaTransdermal lauryl formulations, methods lactate and devices

Approximately thirty chemical compounds have been routinely used by thepharmaceutical industry as permeation enhancers. Most of thesecompounds, however, provide only a slight improvement in absorption.

The known and putative permeation enhancers include members of severalclasses of organic compounds, including: Class Compound(s) Alcoholsethanol; isopropanol; benzyl alcohol Glycols propylene glycol;diethylene glycol monoethyl ether (Transcutol ®) glycol esters glycerolmonolaurate fatty acids oleic acid fatty acid esters isopropyl myristatefatty alcohol esters lauryl lactate; myristyl lactate; cetyl lactate;dodecyl methacrylate miscellaneous DMSO; laurocapram (Azone ®);2-nonyl-1,3-dioxolane (SEPA ®); dodecyl 2-(N,N-dimethylamino) propionate(NexACT ®)

Most of the permeation enhancers fit a common general structure, whichis representative of a non-ionic surface-active agent, i.e., a non-ionicsurfactant. The general structure consists of two discrete portions thatpossess diametrically-opposed physicochemical properties: a polar headand a lipophilic tail. The polar head of the molecule can include one ofa variety of functional groups, as listed above; the lipophilic tailconsists of a hydrocarbon chain that typically ranges from eight tosixteen carbon atoms in length. FIG. 1 illustrates the structures ofeight permeation enhancers (both proprietary and generic) having theaforementioned polar head and lipophilic tail structure.

Of the chemical compounds used as permeation enhancers, one class ofcompounds in particular—fatty alcohol esters of α-hydroxy carboxylicacids (e.g., alkyl lactates)—has found widespread use in cosmetic andpharmaceutical formulations as humectants and/or emollients. This isparticularly true for alkyl lactates where the alkyl group is greaterthan eight carbon atoms in length (i.e., >C₈).

This class of compounds (i.e., fatty alcohol esters of α-hydroxycarboxylic acids)—and specifically dodecyl lactate (also known as lauryllactate), myristyl lacate and cetyl lactate—has also generatedconsiderable interest for application in TDD due to its permeationenhancing properties.

Esters (including fatty alcohol esters) can be prepared using a varietyof traditional techniques. These techniques typically utilize acarboxylic acid (e.g., α-hydroxy carboxylic acid) and alcohol to producethe desired ester.

The following briefly discusses traditional approaches for preparingesters.

Preparation of Esters

Looking next at FIG. 2, most industrial processes for the preparation ofesters (i.e., esterification) involve the reaction of a carboxylic acid5 with an alcohol 10 in the presence of a chemical esterificationcatalyst 15 to produce an ester 20. Chemical esterification catalyst 15is generally an acid or a base, e.g., organic sulfonic acid or metalalkylate. One problem with the ester-producing mechanism shown in FIG. 2is that the esters produced typically contain catalyst residues andby-products, such as difficult-to-remove ethers.

Alternatively, the esterification of a carboxylic acid with an alcoholcan be accomplished via an enzymatic process. In this reaction, which issimilar to the one illustrated in FIG. 2, an enzyme (most often alipase) is used in place of the chemical esterification catalyst 15,typically resulting in a cleaner reaction and, possibly, a higher yieldof pure product. European Patent No. 0383405 (1990) describes the use oflipase in the esterification of C₇-C₃₆ monocarboxylic or dicarboxylicacids with C₂-C₈ alcohols.

FIG. 3 shows a Fischer-type esterification, where carboxylic acid isconverted into an ester in the presence of alcohol and an acid catalyst.In FIG. 3, the Fischer-type esterification is illustrated in the contextof producing the fatty alcohol ester lauryl lactate. More specifically,an α-hydroxy carboxylic acid 25 (e.g., lactic acid, where R═CH₃;α-hydroxypropionic acid) is combined with an alcohol 30 (e.g.,dodecanol, where R′═C₁₂H₂₅) in the presence of a chemical esterificationcatalyst 33 to produce lauryl lactate 35 (where R is CH₃ and R′ isC₁₂H₂₅). This is believed to be a common commercial approach forproducing lauryl lactate.

One problem with this reaction is the potential reactivity of theα-hydroxy group of the α-hydroxy carboxylic acid 25. As a competitivenucleophile in the esterification reaction, involvement of the α-hydroxygroup can result in the formation of polyester (e.g., the polyester 40shown in FIG. 3). Subsequently, lactonization of the polyester 40 mayproduce cyclic ester (e.g., the cyclic ester 45 shown in FIG. 3).

Another problem with this reaction is that the lauryl lactate producedby the Fisher-type esterification can contain as much as 5% dodecanol,as well as intermolecular esterification products (carried over from thecommercial lactic acid 25), and varying amounts of unidentifiedpolymeric species.

While the resulting lauryl lactate is relatively inexpensive to produce,the equivocal quality is directly related to the use of commerciallactic acid as a starting material in the esterification process.Commercial lactic acid is available as an aqueous solution (˜85%), whichcontains varying amounts of intermolecular esterification products. Whensubjected to the harsh conditions of esterification, a complex reactionmixture is inevitable, and often results in the formation of variousby-products. Whereas esterification of lactic acid with dodecanol canalso be accomplished via an arguably milder enzymatic process, theprocess still necessitates the use of lactic acid as a startingmaterial. Therefore, this process will also yield a low purity lauryllactate product.

A review of the literature reveals several other approaches forproducing alkyl lactates (including lauryl lactate).

For example, the synthesis of lauryl lactate using Dawsonphosphotungstic acid catalyst is described in Guangzhou Huaxue 2002,27(1), 32-33, 55 (Chinese). The abstract to this article reported that,under optimum conditions, the yield was greater than 93%. The purity ofthe product was not mentioned.

In another example, described in Xiamen Daxue Xuebao, Ziran Kexueban1997, 36(4), 581-584 (Chinese), various lactate esters were prepared bya Fisher-type esterification. Yields ranged from 81-98%, but the yieldfor lauryl lactate was not specified in the abstract.

In another example, esters of α-hydroxy carboxylic acids were preparedby an enzymatic approach (with lipase as the enzyme). This study wasdescribed in Enzyme and Microbial Technology 1999, 25, 745-752, and itfocused on the optimization of reaction conditions for the syntheses oflactate and glycolate esters of fatty alcohols, including lauryllactate, via esterification of the requisite carboxylic acid.Optimization of the process resulted in the high conversion of lacticacid and dodecanol to lauryl lactate (˜96%). Spanish Patent No. ES2143940, relating to this study, was published in 2000.

While all of the foregoing approaches are capable of producing esters,including fatty alcohol esters and including specifically lauryllactate, they all yield a relatively impure product. This has proven tobe a problem for many applications, including use as a permeationenhancer for TDD.

SUMMARY OF THE INVENTION

One object of the present invention is to provide a new and improvedmethod for making fatty alcohol esters of α-hydroxy carboxylic acids.

A further object of the present invention is to provide a new andimproved method for making fatty alcohol esters of α-hydroxy carboxylicacids, wherein the ester is an alkyl lactate.

Still another object of the present invention is to provide a new andimproved method for making fatty alcohol esters of α-hydroxy carboxylicacids, wherein the ester is lauryl lactate.

Yet another object of the present invention to provide a method formaking fatty alcohol esters of α-hydroxy carboxylic acids that isconvenient, efficient, reproducible, and scalable.

And another object of the present invention to provide a method formaking fatty alcohol esters of α-hydroxy carboxylic acids, wherein thepurity of the product is consistently greater than 95%.

And still another object of the present invention to create a novelfamily of compounds for use as permeation enhancers.

These and other objects are addressed by the provision and use of thepresent invention, which provides a novel approach for the preparationof fatty alcohol esters of α-hydroxy carboxylic acids.

In one form of the invention, the target fatty alcohol ester ofα-hydroxy carboxylic acid is produced by converting a lower alkyl esterof α-hydroxy carboxylic acid into a fatty alcohol ester of α-hydroxycarboxylic acid via alcoholysis (i.e., transesterification). Thetransesterification process is an equilibrium reaction, catalyzedchemically (i.e., with acids or bases) or enzymatically, that is shiftedin the desired direction to produce the desired product. One preferredway of shifting the reaction in the direction of the desired product isby reducing the concentration of one of the products (e.g., distillationof a lower-boiling alcohol as soon as it is formed). Another preferredway of shifting the reaction in the direction of the desired product isby increasing the concentration of one of the reactants (e.g., addingmore of the starting ester).

In another form of the invention, there is provided a method forsynthesizing a fatty alcohol ester of α-hydroxy carboxylic acid,comprising:

converting a lower alkyl ester of α-hydroxy carboxylic acid into a fattyalcohol ester of α-hydroxy carboxylic acid via transesterification,wherein the transesterification process is an equilibrium reaction thatis shifted in the desired direction to produce the desired product.

In another form of the invention, there is provided a method for thesynthesis of high-purity lauryl lactate comprising:

providing:

-   -   a lower-alkyl ester of an α-hydroxy carboxylic acid;    -   an alcohol; and    -   an enzyme; and

converting the lower-alkyl ester of an α-hydroxy carboxylic acid intolauryl lactate through transesterification, wherein thetransesterification process is an equilibrium reaction that is shiftedin the desired direction to produce the desired product.

In another form of the invention, there is provided a fatty alcoholester of α-hydroxy carboxylic acid formed by converting a lower alkylester of α-hydroxy carboxylic acid into a fatty alcohol ester ofα-hydroxy carboxylic acid via transesterification, wherein thetransesterification process is an equilibrium reaction that is shiftedin the desired direction to produce the desired product.

In another form of the invention, there is provided a high-purity lauryllactate formed by (1) providing a lower-alkyl ester of an α-hydroxycarboxylic acid; an alcohol; and an enzyme; and (2) converting thelower-alkyl ester of an α-hydroxy carboxylic acid into lauryl lactatethrough transesterification, wherein the transesterification process isan equilibrium reaction that is shifted in the desired direction toproduce the desired product.

BRIEF DESCRIPTION OF THE DRAWINGS

These and other objects and features of the present invention will bemore fully disclosed or rendered obvious by the following detaileddescription of the preferred embodiments of the invention, which is tobe considered together with the accompanying drawings wherein likenumbers refer to like parts and further wherein:

FIG. 1 shows the structures of eight permeation enhancers;

FIG. 2 is an illustration of a process for the preparation of estersusing a chemical esterification catalyst (e.g., an organic sulfonic acidor a metal alkylate);

FIG. 3 shows a Fischer-type esterification where an α-hydroxy carboxylicacid is converted into an ester in the presence of alcohol and achemical esterification catalyst;

FIG. 4 illustrates a transesterification process in general; and

FIG. 5 shows the transesterification process of the present invention.

DETAILED DESCRIPTION OF THE INVENTION

The present invention provides a novel approach for the preparation offatty alcohol esters of α-hydroxy carboxylic acids.

In one form of the invention, the target fatty alcohol ester ofα-hydroxy carboxylic acid is produced by converting one ester intoanother ester via alcoholysis (i.e., transesterification). Thetransesterification process is an equilibrium reaction, catalyzedchemically (i.e., with acids or bases) or enzymatically, that is shiftedin the desired direction to produce the desired product. One preferredway of shifting the reaction in the direction of the desired product isby reducing the concentration of one of the products (e.g., distillationof a lower-boiling alcohol as soon as it is formed). Another preferredway of shifting the reaction in the direction of the desired product isby increasing the concentration of one of the reactants (e.g., addingmore of the starting ester).

Looking next at FIG. 4, there is shown a general transesterificationprocess. More particularly, in such a process, an ester 50 and alcohol55 are converted into an ester 60 and alcohol 65 using a catalyst 68 todrive the reaction.

Looking next at FIG. 5, the present invention utilizes a similartransesterification process to produce the target fatty alcohol ester ofα-hydroxy carboxylic acid. More particularly, lower-alkyl esters ofα-hydroxy carboxylic acids 70 and primary or secondary alcohols 75 areconverted into fatty alcohol esters 80 and alcohol 85 using anappropriate chemical (i.e., acid or base) or enzyme 90 to catalyze thereaction.

The transesterification process of the present invention offers severaldistinct advantages:

(i) the starting reagents (i.e., lower-alkyl esters of α-hydroxycarboxylic acids 70) are relatively inexpensive, readily available, andof good quality and high purity;

(ii) the product fatty alcohol esters 80 are of high purity(i.e., >95%); and

(iii) the process is amenable to scaling upward.

Various esters of α-hydroxy carboxylic acids 70 may be used. Somepreferred esters of α-hydroxy carboxylic acids 70 are those where:

(i) R₁ is one of the following: H, straight chained or branched alkyl,cycloalkyl, substituted alkyl, arylalkyl, aryl, substituted aryl, andheteroaryl;

(ii) R₂ is either H or alkyl; and

(iii) R₃ is one of the following: C₁-C₄ (e.g., methyl, ethyl,2,2,2-trifluoroethyl, vinyl, propyl, isopropyl, isopropenyl, butyl,isobutyl, sec-butyl or tert-butyl).

In particular, the ethyl esters of glycolic acid, lactic acid, mandelicacid, 2-hydroxyisobutyric acid, and 2-hydroxycaproic acid are preferred.

Various alcohols 75 may be used. Some preferred alcohols 75 arestraight-chain alcohols where R₄ is an alkyl group greater than or equalto an eight carbon chain (i.e., ≧C₈). Other suitable alcohols can beprimary or secondary, can be branched, can contain various substituents(other than hydroxyl), and can be monounsaturated or polyunsaturated.

In particular, fatty alcohols such as 1-dodecanol, 2-dodecanol,1-tetradecanol, and 1-hexadecanol are preferred.

Various chemicals (i.e., acids or bases) and enzymes 90 may be used.Some preferred enzymes are lipases. In particular, lipases obtained fromthe following well-known microorganisms are preferred: Aspergillusspecies, Rhizopus species, Penicillum species, Candida species,Pseudomonas species, Mucor species, and Humicola species.

It is preferred (but not necessarily required) that the lipase beimmobilized by attachment to a suitable water-insoluble inorganic ororganic material such as silica, ion exchange resins, acrylate resins,porous polystyrene, etc.

The transesterification process is an equilibrium reaction, catalyzedchemically (i.e., with acids or bases) or enzymatically, that is shiftedin the desired direction to produce the desired product. One preferredway of shifting the reaction in the direction of the desired product isby reducing the concentration of one of the products (e.g., distillationof a lower-boiling alcohol as soon as it is formed). Another preferredway of shifting the reaction in the direction of the desired product isby increasing the concentration of one of the reactants (e.g., addingmore of the starting ester).

In one preferred form of the invention, the transesterification reactionis conducted in such a way that alcohol formed in the course of thereaction is removed from the reaction medium. Alcohol removal can beaccomplished in a variety of ways apparent to those skilled in the artincluding, but not limited to evaporation under ambient conditions,evaporation facilitated by heat, convection, inert gas flow, applicationof vacuum, distillation (including azeotropic and vacuum distillation,chemical or enzymatic modification, adsorption, etc.

The transesterification reaction of the present invention can also beaccomplished by any technique that facilitates the interaction of thereactants and results in the formation of product and the generation ofalcohol.

In one embodiment, the reactants (i.e., the lower-alkyl ester ofα-hydroxy carboxylic acid 70 and the alcohol 75) are combined such thatthe amount of ester present relative to the amount of alcohol present isat least an equimolar amount, and may represent a two-to-tenfold orhigher molar excess. The reactants are combined in a vessel ofappropriate size and design such that controlled heating and stirring isallowed, and from which the reaction mixture can be easily removed. Theenzyme 90 is added in an amount that is typically between about 0.10 toabout 2 times the weight of the alcohol 75. The reactants are stirred atan appropriate speed for twelve to forty-eight hours with controlledheating from about 30-90° C.

In another embodiment of the present invention, the reactants (i.e., thelower-alkyl ester of α-hydroxy carboxylic acid 70 and the alcohol 75)are combined such that the amount of ester present relative to theamount of alcohol present is at least an equimolar amount, and mayrepresent a two-to-tenfold or higher molar excess. The reactants arecombined in a vessel of appropriate size and design such that controlledheating and stirring is allowed, and from which the reaction mixture canbe easily removed. The enzyme 90 is added in an amount that is betweenabout 0.10 to about 2.0 times the weight of the alcohol 75. In thisembodiment, a fourth substance, i.e., an absorbing agent (e.g. molecularsieves, silica gel, etc.), is added in an amount that is between two tofive times the weight of the alcohol. The reactants are stirred at anappropriate speed for twelve to forty-eight hours with controlledheating from about 30-90° C.

In another embodiment of the present invention, the reactants (i.e., thelower-alkyl ester of α-hydroxy carboxylic acid 70 and the alcohol 75)are combined such that the amount of ester present relative to theamount of alcohol present is at least an equimolar amount, and mayrepresent a two-to-tenfold or higher molar excess. The reactants arecombined in a vessel of appropriate size and design such that controlledheating and stirring is allowed, and from which the reaction mixture canbe easily removed. The enzyme 90 is added in an amount that is betweenabout 0.10 to about 2.0 times the weight of the alcohol. An absorbingagent (e.g., molecular sieves, silica gel, etc.) may be added in anamount that is between two to five times the weight of the alcohol 75.The reactants are stirred at an appropriate speed for twelve toforty-eight hours with controlled heating from about 30-90° C. Thealcohol generated during the reaction is removed by distillation byreducing the pressure in the system through the application of a weakvacuum.

In another embodiment of the present invention, the reactants (i.e., thelower-alkyl ester of α-hydroxy carboxylic acid 70 and the alcohol 75)are combined such that the amount of ester present relative to theamount of alcohol present is at least an equimolar amount, and mayrepresent a two-to-tenfold or higher molar excess. The reactants arecombined in a vessel of appropriate size and design such that controlledheating and stirring is allowed, and from which the reaction mixture canbe easily removed. In this embodiment, a solvent is added in a volume of100-1000 ml/mole of alcohol. Suitable solvents include acetone,acetonitrile, dioxane, heptane, hexanes, and tetrahydrofuran. The enzyme90 is added in an amount that is between about 0.10 to about 2.0 timesthe weight of the alcohol 75. An absorbing agent (e.g., molecularsieves, silica gel, etc.) may be added in an amount that is between twoto five times the weight of the alcohol. The reactants are stirred at anappropriate speed for twelve to forty-eight hours with controlledheating from about 30-90° C. The alcohol generated during the reactionis removed by co-distillation with solvent by reducing the pressure inthe system through the application of a weak vacuum. Additional solventis added to the system at approximately the same rate as distillate isformed.

In another embodiment of the present invention, the reactants (i.e., thelower-alkyl ester of α-hydroxy carboxylic acid 70 and the alcohol 75)are combined in a vessel of appropriate size and design such thatcontrolled heating and stirring is allowed, and from which the reactionmixture can be easily removed. The alcohol 75 and enzyme 90 are combinedsuch that the enzyme is present in an amount that is between about 0.10to about 2.0 times the weight of the alcohol. A solvent is added in avolume of 100-1000 ml/mole of alcohol. Suitable solvents includeacetone, acetonitrile, dioxane, heptane, hexanes, and tetrahydrofuran.An absorbing agent (e.g., molecular sieves, silica gel, etc.) may beadded in an amount that is between two to five times the weight of thealcohol. The reactants are stirred at an appropriate speed withcontrolled heating from about 30-90° C. while reducing the pressure inthe system through the application of a weak vacuum. The ester 70 isadded slowly by means of an addition funnel or syringe pump until anequimolar amount or slight molar excess of ester has been added. Thealcohol 85 generated during the reaction is removed by co-distillationwith solvent. Additional solvent is added to the system at approximatelythe same rate as distillate is formed.

In another embodiment of the present invention, the reactants (i.e., thelower-alkyl ester of α-hydroxy carboxylic acid 70 and the alcohol 75)are combined in a vessel of appropriate size and design such thatcontrolled heating and stirring is allowed, and from which the reactionmixture can be easily removed. The ester 70 and enzyme 90 are combinedsuch that the quantity of ester is an amount that represents atwo-to-tenfold or higher molar excess based on the quantity of alcohol75 to be used. The enzyme 90 is present in an amount that is betweenabout 0.10 to about 2.0 times the weight of the alcohol to be used.Optionally, a solvent is added in a volume of 100-1000 ml/mole ofalcohol to be used. Suitable solvents include acetone, acetonitrile,dioxane, heptane, hexanes, and tetrahydrofuran. An absorbing agent(e.g., molecular sieves, silica gel, etc.) may be added in an amountthat is between two to five times the weight of the alcohol. Thereactants are stirred at an appropriate speed with controlled heatingfrom about 30-90° C. while reducing the pressure in the system throughthe application of a weak vacuum. The alcohol 75 is added slowly bymeans of an addition funnel or syringe pump. The alcohol 85 generatedduring the reaction is removed by distillation or co-distillation with asolvent. As needed, additional solvent is added to the system atapproximately the same rate as distillate is formed.

In another embodiment of the present invention, the reactants (i.e., thelower-alkyl ester of α-hydroxy carboxylic acid 70 and the alcohol 75)are combined in a vessel of appropriate size and design such thatcontrolled heating and stirring is allowed, the ester 70 and alcohol 75are combined such that the quantity of ester used is an amount thatrepresents a two-to-tenfold or higher molar excess based on the quantityof alcohol. The mixture is maintained at about 50-90° C. while stirring,and liquid from the reservoir is pumped continuously through a columnpacked with immobilized enzyme 90 and maintained at about 50-70° C.,then returned to the reservoir. Alcohol 85 produced during the reactionin the packed-bed column reactor is removed from the reservoir throughevaporation or distillation by reducing the pressure in the reservoir bythe application of a weak vacuum.

In another embodiment of the present invention, a mixture of alcohol 75(X moles), ester 70 (1-5× moles), enzyme 90 (0.6×186.34×), and molecularsieves (5×186.34×), is placed in a stainless steel container ofappropriate size such that the bed depth of the mixture does not exceed1.5″, with a preferred depth of 1″. The container is placed in aconvection oven at 60±5° C. for a time sufficient to consume greaterthan 95% of the alcohol 75. The time required is dependent upon thereaction size, and may be determined by monitoring the reactionperiodically by high performance liquid chromatography (HPLC) or gaschromatography (GC).

In another embodiment of the present invention, a mixture of alcohol 75(1-dodecanol, X moles), ester 70 (ethyl lactate, 5× moles), enzyme 90(Novozym® 435, 0.6×186.34×), and molecular sieves (5×186.34×) is placedin a stainless steel container of appropriate size such that the beddepth of the mixture does not exceed 1.5″, with a preferred depth of 1″.The container is placed in a convection oven at 60° C. for a timesufficient to consume greater than 98% of the 1-dodecanol. The timerequired is dependent upon the reaction size, and may be determined bymonitoring the reaction periodically by HPLC-RI. Once the reaction hasprogressed satisfactorily, the container is removed from the oven and,after cooling to ambient temperature, the contents of the container aretransferred to a larger container for the purpose of adding solvent.Adequate solvent is added to the container so that most of the productis solubilized. Solvents may be chosen from the group of lower molecularweight hydrocarbons, which may include pentane, petroleum ether,hexanes, heptane and isooctane. The solution of product in thehydrocarbon solvent is isolated by vacuum filtration, and transferred toa separatory funnel of adequate size to allow washing with an equalvolume of water. The water wash is repeated two more times, and then theorganic phase is washed with brine. The final organic solution is driedover magnesium sulfate to remove residual water. At this point,activated carbon may be added so as to render the solution nearlycolorless. The dried, carbon-treated solution is isolated by vacuumfiltration employing a filtration aid, preferably Celite®. The solutionis concentrated by rotary evaporation until most of the solvent has beenremoved. Residual solvent can be removed by storing the product undervacuum, preferably 29″ Hg, preferably at a temperature not to exceed 30°C.

In another embodiment of the present invention, a multi-kilogram batchof lauryl lactate is produced in the absence of molecular sieves. Theprocess involves a mixture of alcohol 75 (1-dodecanol, 4000 mL), ester70 (ethyl lactate, 4000 mL, 2 molar equivalents), and enzyme 90(Novozym® 435, 1000 g). The mixture is placed in a 50 L glass pilotplant reactor and is stirred at 60±5° C. for 28-32 hours. (Note: thetime required may be determined by monitoring the reaction periodicallyby HPLC-RI or GC-FID.) Once the reaction has progressed satisfactorily,the reaction mixture is filtered through a semi-permeable nylon bag toisolate the enzyme, and the filtrate is returned to the reactor where itis diluted with petroleum ether (4 L). The mixture is washed with brine(2 L) by adding the brine to the reactor, stirring for 1-2 minutes,allowing phase separation to occur, and then drawing off the loweraqueous phase to waste. The brine wash is repeated, and then the mixtureis washed with water (4×2 L) in similar fashion. After the final waterwash, the mixture is washed again with brine (2 L). Then MgSO₄ (100 g)and activated carbon (50 g) are added to the washed organic mixture, andthe mixture is stirred for 1 hour at room temperature (RT). The mixtureis filtered through a glass fiber filter and the filtrate isconcentrated by rotary evaporation until most of the solvent has beenremoved. Residual solvent can be removed by storing the product undervacuum, preferably 29″ Hg, preferably at a temperature not to exceed 30°C.

The following non-limiting examples provide methods for preparing fattyalcohol esters of α-hydroxy carboxylic acids. The specific examples thatfollow are representative of the potential of the present invention andare not to be construed as limiting the invention in sphere or scope.The methods may be adapted to variation in order to produce productsembraced by this invention but not specifically disclosed. Furthervariations of the methods to produce the same products in somewhatdifferent fashion will be evident to one skilled in the art.

EXAMPLE 1

A mixture of enzyme (275.07 g; lipase B from Candida antarcticaimmobilized on macroporous acrylic resin beads; Novozym® 435), molecularsieves (2301 g), 1-dodecanol (551 mL), and ethyl lactate (1400 mL) in a12″×20″ stainless steel tray (bed depth 1.25″) was maintained at 60° C.in a convection oven for 32 hour. Upon work-up, 538 g of lauryl lactate(83% yield) was obtained as a pale yellow liquid. The purity of theproduct was >95% as assessed by HPLC-RI.

EXAMPLE 2

A mixture of Novozym® 435 (2.21 g), molecular sieves (18.60 g),1-dodecanol (3.76 g), and ethyl mandelate (3.61 g) in a 150 mL beakerwas maintained at 60° C. in a convection oven for 28 hours. Uponwork-up, 4.0 g of lauryl mandelate (56% yield) was obtained as a clearviscous liquid. The purity of the product was >95% as assessed byHPLC-DAD.

EXAMPLE 3

A mixture of Novozym 435 (2.81 g), molecular sieves (23.17 g),3,7-dimethyl-1-octanol (4.64 g), and ethyl lactate (14.78 g) in a 250 mLbeaker was maintained at 60° C. in a convection oven for 28 hours. Uponwork-up, 4.2 g of 3,7-dimethyl-1-octyl lactate (62% yield) was obtainedas an amber-colored liquid. The purity of the product was >96% asassessed by HPLC-RI.

EXAMPLE 4

A mixture of Novozym® 435 (2.43 g), molecular sieves (20.17 g),1-octadecanol (4.04 g), and ethyl lactate (8.86 g) in a 150 mL beakerwas maintained at 60° C. in a convection oven for 28 hours. Uponwork-up, 2.0 g of cetyl lactate (40% yield) was obtained as a waxy whitesolid. The purity of the product was >98% as assessed by HPLC-RI.

EXAMPLE 5

A mixture of Novozym® 435 (1 kg), 1-dodecanol (2000 mL), and ethyllactate (2000 mL) in a 50 L reactor was stirred (˜200 rpm) at 60±5° C.for 28 hours. Upon work-up, 2000 g of lauryl lactate (80% yield) wasobtained as a pale yellow liquid. The purity of the product was >97% asassessed by GC.

EXAMPLE 6

A mixture of Novozym® 435 (8.02 g), 1-dodecanol (13.01 g), ethyl lactate(8.70 mL) and acetonitrile (8.70 mL) was placed in a 100 mL three-neck,round bottom flask containing a stir bar. The flask was equipped with anaddition funnel charged with acetonitrile, a stopper, and a short pathdistillation head, which was connected to a vacuum pump. The flask wasplaced in an oil bath, and the mixture was magnetically stirred at 80±5°C. Additional acetonitrile was added as needed based upon the amount ofdistillate collected. After 42 hours, analysis of the reaction mixtureby GC-FID indicated >96% lauryl lactate.

EXAMPLE 7

A mixture of Novozym® 435 (8.01 g), 1-dodecanol (18.63 g), and hexanes(50 mL) was placed in a 250 mL three-neck, round bottom flask containinga stir bar. The flask was equipped with an addition funnel charged withethyl lactate (25 mL), a stopper, and a short path distillation head,which was connected to a vacuum pump. The flask was placed in an oilbath, and the mixture was magnetically stirred at 80±5° C. As distillatebegan to collect, the slow dropwise addition of ethyl lactate was begun.Additional hexanes were added as needed. After 42 hours, analysis of thereaction mixture by GC-FID indicated >95% lauryl lactate.

EXAMPLE 8

A mixture of Novozym® 435 (5.99 g), 1-dodecanol (14.01 g), and hexanes(40 mL) was placed in a 250 mL three-neck, round bottom flask containinga stir bar. The flask was equipped with an addition funnel charged withhexanes, a rubber septum, and a short path distillation head, which wasconnected to a vacuum pump via an acetone-dry ice condenser. Ethyllactate (15 mL) was drawn into a 20 mL syringe, which was secured in asyringe pump. The pump was programmed to deliver 10 mL of ethyl lactateat a rate of 1.0 mL/h. The syringe needle was inserted through therubber septum, and the flask was placed in an oil bath. The mixture wasmagnetically stirred at 80±5° C. As distillate began to collect, theaddition of ethyl lactate was begun. Hexanes were added dropwise at arate approximating the rate at which distillate was collected. After 12hours, all devices were turned off and the reaction mixture stoodovernight at room temperature (RT). Analysis of the reaction mixture byGC-FID indicated >95% lauryl lactate.

EXAMPLE 9

Novozym® 435 (250-300 g), molecular sieves (2250-2350 g), 1-dodecanol(540-560 mL), and ethyl lactate (1350-1450 mL) were mixed together in a12″×20″ stainless steel tray (bed depth ˜1.25″). A total of four trayswere prepared in parallel, and maintained at 60° C. in a convection ovenfor 32 hours. After cooling to ambient temperature, the contents of eachtray were diluted with petroleum ether, and the enzyme/sieves mixturewas removed by vacuum filtration. The combined filtrates weretransferred to a 50 L reactor and processed accordingly. Upon work-up,2024 g of lauryl lactate (78% yield) was obtained as a pale yellowliquid. The purity of the product was >98% as assessed by HPLC-RI.

EXAMPLE 10

A mixture of Novozym® 435 (500 g), 1-dodecanol (2000 mL), and ethyllactate (2000 mL) in a 5 L reactor was stirred (˜200 rpm) at 60±5° C.for 28 hours. Upon work-up, 2000 g of lauryl lactate (>80% yield) wasobtained as a pale yellow liquid. The purity of the product was >95% asassessed by GC-FID.

EXAMPLE 11

A mixture of Novozym® 435 (1 kg), 1-dodecanol (4000 mL), and ethyllactate (4000 mL) in a 50 L reactor was stirred (˜200 rpm) at 60±5° C.for 28 hours. Upon work-up, 4000 g of lauryl lactate (80% yield) wasobtained as a pale yellow liquid. The purity of the product was >97% asassessed by GC.

Modifications

It is to be understood that the present invention is by no means limitedto the particular constructions herein disclosed and/or shown in thedrawings, but also comprises any modifications or equivalents within thescope of the invention.

1. A method for synthesizing a fatty alcohol ester of α-hydroxycarboxylic acid, comprising: converting a lower alkyl ester of α-hydroxycarboxylic acid into a fatty alcohol ester of α-hydroxy carboxylic acidvia transesterification, wherein the transesterification process is anequilibrium reaction that is shifted in the desired direction to producethe desired product.
 2. A method according to claim 1 wherein thetransesterification process is catalyzed chemically.
 3. A methodaccording to claim 2 wherein the transesterification process iscatalyzed with an acid.
 4. A method according to claim 2 wherein thetransesterification process is catalyzed with a base.
 5. A methodaccording to claim 1 wherein the transesterification process iscatalyzed with an enzyme.
 6. A method according to claim 5 wherein theenzyme is a lipase.
 7. A method according to claim 6 wherein the lipaseis obtained from a microorganism selected from the group consisting of:Aspergillus species, Rhizopus species, Penicillum species, Candidaspecies, Pseudomonas species, Mucor species, and Humicola species.
 8. Amethod according to claim 6 wherein the the lipase is immobilized byattachment to a suitable water-insoluble material.
 9. A method accordingto claim 8 wherein the suitable water-insoluble material is selectedfrom the group consisting of: silica, ion exchange resins, acrylateresins and porous polystyrene.
 10. A method according to claim 1 whereinthe equilibrium reaction is shifted in the direction of the desiredproduct by reducing the concentration of one of the products of thetransesterification process.
 11. A method according to claim 10 whereinthe concentration of one of the products of the transesterificationprocess is removed by using at least one of the following: evaporationunder ambient conditions, evaporation facilitated by heat, rotaryevaporation, convection, inert gas flow, application of a vacuum, vacuumfiltration, distillation; azeotropic distillation, vacuum distillation;chemical modification, enzymatic modification and adsorption.
 12. Amethod according to claim 10 wherein one of the products of thetransesterification process is an alcohol, and further wherein theconcentration of that alcohol is reduced by distillation.
 13. A methodaccording to claim 1 wherein the equilibrium reaction is shifted in thedirection of the desired product by increasing the concentration of oneof the reactants of the transesterification process.
 14. A methodaccording to claim 13 wherein the equilibrium reaction is shifted in thedirection of the desired product by adding more of the lower alkyl esterof α-hydroxy carboxylic acid.
 15. A method according to claim 1 whereinthe lower alkyl ester of α-hydroxy carboxylic acid is represented by thefollowing formula:

wherein R₁ is selected from the group consisting of: H, straight chainedor branched alkyl, cycloalkyl, substituted alkyl, arylalkyl, aryl,substituted aryl and heteroaryl; R₂ is selected from the groupconsisting of: H and alkyl; and R₃ is selected from the group consistingof: methyl, ethyl, 2,2,2-trifluoroethyl, vinyl, propyl, isopropyl,isopropenyl, butyl, isobutyl, sec-butyl and tert-butyl.
 16. A methodaccording to claim 1 wherein the lower alkyl ester of α-hydroxycarboxylic acid is selected from the group consisting of: the ethylesters of glycolic acid, lactic acid, mandelic acid, 2-hydroxyisobutyricacid, 2-hydroxycaproic acid, ethyl lactate and ethyl mandelate.
 17. Amethod according to claim 1 wherein the transesterification processcomprises combining the lower alkyl ester of α-hydroxy carboxylic acidwith an alcohol.
 18. A method according to claim 17 wherein the alcoholis a straight-chain alcohol represented by the following formula:R₄OH wherein R₄ is an alkyl group greater than or equal to an eightcarbon chain.
 19. A method according to claim 17 wherein the alcohol isselected from the group consisting of primary, secondary, branched,monounsaturated and polyunsaturated alcohols.
 20. A method according toclaim 17 wherein the alcohol contains a substituent other than hydroxyl.21. A method according to claim 17 wherein the alcohol is selected fromthe group consisting of: 1-dodecanol, 2-dodecanol, 1-tetradecanol,1-hexadecanol, 3,7-dimethyl-l-octanol and 1-octadecanol.
 22. A methodaccording to claim 1 wherein the fatty alcohol ester of α-hydroxycarboxylic acid is lauryl lactate.
 23. A method according to claim 22wherein the lauryl lactate has a purity >95%.
 24. A method for thesynthesis of high-purity lauryl lactate comprising: providing: alower-alkyl ester of an α-hydroxy carboxylic acid; an alcohol; and anenzyme; and converting the lower-alkyl ester of an α-hydroxy carboxylicacid into lauryl lactate through transesterification, wherein thetransesterification process is an equilibrium reaction that is shiftedin the desired direction to produce the desired product.
 25. A methodaccording to claim 24 wherein the enzyme is a lipase.
 26. A methodaccording to claim 25 wherein the lipase is obtained from amicroorganism selected from the group consisting of: Aspergillusspecies, Rhizopus species, Penicillum species, Candida species,Pseudomonas species, Mucor species, and Humicola species.
 27. A methodaccording to claim 25 wherein the the lipase is immobilized byattachment to a suitable water-insoluble material.
 28. A methodaccording to claim 27 wherein the suitable water-insoluble material isselected from the group consisting of: silica, ion exchange resins,acrylate resins and porous polystyrene.
 29. A method according to claim24 wherein the equilibrium reaction is shifted in the direction of thedesired product by reducing the concentration of one of the products ofthe transesterification process.
 30. A method according to claim 29wherein the concentration of one of the products of thetransesterification process is removed by using at least one of thefollowing: evaporation under ambient conditions, evaporation facilitatedby heat, rotary evaporation, convection, inert gas flow, application ofa vacuum, vacuum filtration, distillation; azeotropic distillation,vacuum distillation; chemical modification, enzymatic modification andadsorption.
 31. A method according to claim 29 wherein one of theproducts of the transesterification process is an alcohol, and furtherwherein the concentration of that alcohol is reduced by distillation.32. A method according to claim 24 wherein the equilibrium reaction isshifted in the direction of the desired product by increasing theconcentration of one of the reactants of the transesterificationprocess.
 33. A method according to claim 32 wherein the equilibriumreaction is shifted in the direction of the desired product by addingmore of the lower alkyl ester of α-hydroxy carboxylic acid.
 34. A methodaccording to claim 24 wherein the lower alkyl ester of α-hydroxycarboxylic acid is represented by the following formula:

wherein: R₁ is selected from the group consisting of: H, straightchained or branched alkyl, cycloalkyl, substituted alkyl, arylalkyl,aryl, substituted aryl and heteroaryl; R₂ is selected from the groupconsisting of: H and alkyl; and R₃ is selected from the group consistingof: methyl, ethyl, 2,2,2-trifluoroethyl, vinyl, propyl, isopropyl,isopropenyl, butyl, isobutyl, sec-butyl and tert-butyl.
 35. A methodaccording to claim 24 wherein the lower alkyl ester of α-hydroxycarboxylic acid is selected from the group consisting of: the ethylesters of glycolic acid, lactic acid, mandelic acid, 2-hydroxyisobutyricacid, 2-hydroxycaproic acid, ethyl lactate and ethyl mandelate.
 36. Amethod according to claim 24 wherein the alcohol is a straight-chainalcohol represented by the following formula:R₄OH wherein R₄ is an alkyl group greater than or equal to an eightcarbon chain.
 37. A method according to claim 24 wherein the alcohol isselected from the group consisting of primary, secondary, branched,monounsaturated and polyunsaturated alcohols.
 38. A method according toclaim 24 wherein the alcohol contains a substituent other than hydroxyl.39. A method according to claim 24 wherein the alcohol is selected fromthe group consisting of: 1-dodecanol, 2-dodecanol, 1-tetradecanol,1-hexadecanol, 3,7-dimethyl-1-octanol and 1-octadecanol.
 40. A methodaccording to claim 24 wherein the lauryl lactate has a purity >95%. 41.A method according to claim 6 wherein the lipase is not immobilized. 42.A method according to claim 25 wherein the lipase is not immobilized.43. A method according to claim 1 wherein the fatty alcohol ester ofα-hydroxy carboxylic acid is lauryl mandelate.
 44. A method according toclaim 1 wherein the fatty alcohol ester of α-hydroxy carboxylic acid is3,7-dimethyl-1-octyl lactate.
 45. A method according to claim 1 whereinthe fatty alcohol ester of α-hydroxy carboxylic acid is cetyl lactate.46. A method according to claim 1 wherein the fatty alcohol ester ofα-hydroxy carboxylic acid is ethyl lactate.
 47. A method according toclaim 1 wherein an absorbing agent is added to the reaction.
 48. Amethod according to claim 24 wherein an absorbing agent is added to thereaction.
 49. A method according to claim 1 wherein a solvent is addedto the reaction.
 50. A method according to claim 49 wherein the solventis selected from a group consisting of the following: acetone,acetonitrile, dioxane, heptane, hexanes and tetrahydrofuran.
 51. Amethod according to claim 24 wherein a solvent is added to the reaction.52. A method according to claim 51 wherein the solvent is selected froma group consisting of the following: acetone, acetonitrile, dioxane,heptane, hexanes and tetrahydrofuran.
 53. A fatty alcohol ester ofα-hydroxy carboxylic acid formed by converting a lower alkyl ester ofα-hydroxy carboxylic acid into a fatty alcohol ester of α-hydroxycarboxylic acid via transesterification, wherein the transesterificationprocess is an equilibrium reaction that is shifted in the desireddirection to produce the desired product.
 54. A high-purity lauryllactate formed by (1) providing a lower-alkyl ester of an α-hydroxycarboxylic acid; an alcohol; and an enzyme; and (2) converting thelower-alkyl ester of an α-hydroxy carboxylic acid into lauryl lactatethrough transesterification, wherein the transesterification process isan equilibrium reaction that is shifted in the desired direction toproduce the desired product.